Ferric citrate dosage forms

ABSTRACT

Disclosed herein are ferric citrate-containing tablets. In various embodiments, the tablets include ferric citrate formulations that meet certain dissolution, tableting and disintegration standards. In various aspects, the tablet formulations can include ferric citrate as the active ingredient and a binder. The formulations also can include a lubricant and/or a disintegrant (which, in some embodiments, can be the same as the binder).

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a divisional of U.S. patent application Ser. No.13/255,326, filed Sep. 8, 2011, which is a national stage ofInternational Patent Application No. PCT/US2010/042788, filed Jul. 21,2010, which claims priority to U.S. Provisional Patent Application No.61/227,124, filed Jul. 21, 2009, each of which is hereby incorporated byreference herein for all purposes in their entirety.

FIELD

The field of the disclosure generally relates to pharmaceuticalcompositions of ferric citrate, methods for their use in treatingmedical conditions, and processes for their manufacture.

BACKGROUND

U.S. Pat. No. 5,753,706 discloses that ferric citrate compounds can beused to control phosphate metabolism and prevent metabolic acidosis inpatients. The contents of U.S. Pat. No. 5,753,706 are incorporatedherein in its entirety by reference. Ferric citrate compounds can beused with patients suffering from renal failure associated withhyperphosphatemia or patients predisposed to development of ahyperphosphatemic condition. Ferric citrate also is used as a foodsupplement and additive. Ferric citrate is characterized as a lightbrown to beige powder, odorless and slightly ferruginous tasting.According to the Merck Index, ferric citrate is slowly but completelysoluble in cold water and readily soluble in hot water but diminishes insolubility with age.

U.S. Pat. No. 6,903,235 discloses that ferric citrate is commerciallyavailable in the form of a combination of iron and citric acid ofindefinite composition. The contents of U.S. Pat. No. 6,903,235 areincorporated herein in its entirety by reference. The '235 Patentexplains that the indefinite composition is likely due to difficultiesencountered in its preparation but that those knowledgeable in the artunderstand and necessarily accept that commercially available ferriccitrate contains different molar ratios of iron and citric acid and alsocontains different amounts of water.

WO 2004/074444 discloses processes for making ferric organic compounds,such as ferric citrate, with enhanced dissolution rates. WO 2007/022435is a continuation-in-part of WO 2004/074444 and discloses processes formaking ferric organic compounds soluble over a wide pH range and havinga large surface area. WO 2007/089577 is directed to methods of treatingsoft tissue calcification using ferric organic compounds, such as aferric citrate compound. WO 2007/089571 is directed to methods oftreating chronic kidney disease using ferric organic compounds, such asferric citrate compounds.

SUMMARY

In one aspect, the disclosure is directed to a tablet including ferriccitrate. In some embodiments, the tablet can include at least 65 weightpercent ferric citrate.

In another aspect, the disclosure is directed to a tablet comprisinggranule particles. The granule particles include ferric citrate and abinder, and the mean surface area to mass ratio of the granule particlesis equal to or greater than 1 m² per gram. In various embodiments, themean surface area to mass ratio of said granule particles is equal to orgreater than 5 m² per gram or 10 m² per gram.

In another aspect, the tablet can include at least 70 weight percentferric citrate, at least 80 weight percent ferric citrate, or at least90 weight percent ferric citrate.

In another aspect, the binder can be one or more of hydroxypropylcellulose (HPC), hydroxypropylmethyl cellulose (HPMC), sodium alginate,alginic acid, guar gum, acacia gum, xanthan gum, carbolpol, cellulosegum (carboxymethyl cellulose), ethyl cellulose, maltodextrin, PVP/VA,povidone, microcrystalline cellulose, starch (partially or fullypregelatinized starch) and methyl cellulose.

In another aspect, the tablet can include various additional componentsincluding, for example, one or more disintegrants and/or one or morelubricants. The disintegrant can be one or more of microcrystallinecellulose, croscarmellose sodium, crospovidone, sodium starch glycolate,and starch. The lubricant can be one or more of magnesium stearate,calcium stearate, sodium stearyl fumarate, polyethylene glycol(molecular weight above 3350), sodium lauryl sulfate, talc, mineral oil,leucine, and poloxamer. In some embodiments, the tablet can includebetween approximately 65% and 92% ferric citrate, between approximately4.5% and 30% binder, and between 0.5% and 3% lubricant. The binder canhave disintegrant properties. The binder can be pregelatinized starch.

In another aspect, the tablet can be between approximately 65% and 92%ferric citrate, between approximately 4.5% and 30% binder, betweenapproximately 1.5% and 15% disintegrant, and between 0.5% and 3%lubricant.

Various additional components in the tablet can include microcrystallinecellulose, pregelatinized starch and sodium stearyl fumarate. In oneembodiment, the ferric citrate can be present at approximately 85 weightpercent, the microcrystalline cellulose present at approximately 4weight percent, the pregelatinized starch present at approximately 9weight percent, and the sodium stearyl fumarate present at approximately2 weight percent.

In another aspect, the tablet can have between approximately 10% and 60%of ferric citrate dissolved in about 15 minutes, between approximately30% and 90% of ferric citrate dissolved in about 30 minutes and at leastapproximately 60% of the ferric citrate dissolved in about 60 minutes ina dissolution test according to test method USP <711>. The tablet canhave a dissolution of at least 90% within 30 minutes in a dissolutiontest according to test method USP <711>. The tablet can show adissolution of at least 90% within 60 minutes in a dissolution testaccording to test method USP <711>.

The tablet can show a disintegration time of less than 30 minutes in adisintegration test according to test method USP <701>. The tablet canshow a disintegration time of greater than 30 minutes in adisintegration test according to test method USP <701>.

The tablet can include approximately 1000 mg of ferric citrate,approximately 667 mg of ferric citrate, approximately 500 mg of ferriccitrate, approximately 250 mg of ferric citrate, or approximately 125 mgof ferric citrate.

In various aspects, the LOD (loss on drying) % water in the tablet isless than 20% water w/w. In other aspects, the LOD % water of the tabletis less than 15% water w/w. In still other aspects, the LOD % water ofthe tablet is less than 10% water w/w.

In various aspects, at least 80% of the ferric citrate in the tablet isdissolved in a time less than or equal to 60 minutes as measured by testmethod USP <711>.

In another aspect, the tablet includes a disintegrant. In certainembodiments, the disintegrant can be selected from one or more ofmicrocrystalline cellulose, croscarmellose sodium, crospovidone, sodiumstarch glycolate, and starch.

In another aspect, the tablet includes a lubricant. In certainembodiments, the lubricant can be selected from one or more of magnesiumstearate, calcium stearate, and sodium stearyl fumarate.

In another aspect, the disclosure is directed to a method of preparing aferric citrate tablet. The method includes mixing the ferric citratewith one or more binders under conditions in which the LOD % water doesnot exceed 25% to form ferric citrate granules. Granulation can beperformed by any method known in the art (e.g., fluid bed granulation orhigh shear granulation). The ferric citrate granules are then tableted.

In another aspect, the tablets are heated to above 50° C. aftertableting.

The tablets can be used for the prophylaxis or treatment of a variety ofdiseases or disease states, including, but not limited to,hyperphosphatemia.

Embodiments of the method can include one or more of the featuresdescribed above or herein.

The details of various embodiments are set forth in the accompanyingdrawings and the description below. Features and advantages of variousembodiments are apparent from the description, the drawings, and theclaims.

DESCRIPTION OF THE DRAWINGS

Those skilled in the art will understand that the drawings, describedherein, are for illustration purposes only. The drawings are notintended to limit the scope of the present disclosure.

FIG. 1 depicts a Tablet Friability Apparatus.

FIG. 2 is a chart showing hardness as a function of compression forcefor Formulations 1-5.

FIG. 3 is a chart showing friability as a function of compression forcefor Formulations 1-5.

FIG. 4 is a chart showing disintegration time as a function ofcompression force for Formulations 1-5.

FIG. 5 is a chart showing dissolution time for Formulations 1 and 3-5.

FIG. 6 is a chart showing hardness as a function of compression forcefor Formulations 6-8 and 11.

FIG. 7 is a chart showing friability as a function of compression forcefor Formulations 6-8 and 11.

FIG. 8 is a chart showing disintegration time as a function ofcompression force for Formulations 6-8 and 11.

FIG. 9 is a chart showing dissolution time for Formulations 6-8 and 11.

FIG. 10 shows the dissolution time for different tablets that werepre-dried and post-dried.

DETAILED DESCRIPTION

Disclosed herein are ferric citrate-containing tablets. In variousembodiments, the tablets include ferric citrate formulations that meetcertain dissolution, tableting and disintegration standards. In variousaspects, the tablet formulations can include ferric citrate as theactive ingredient and a binder. The formulations also can include alubricant and/or a disintegrant (which, in some embodiments, can be thesame as the binder).

Tablets

In one aspect, the formulation is a tablet that includes ferric citrateand a binder. As is used herein, a “tablet” is a material produced bycompression force, such as with a tableting machine. In otherembodiments the formulation or tablet can include ferric citrate, abinder, a lubricant and a disintegrant. The tablet or formulation can beused as a prophylaxis or treatment for hyperphosphatemia byadministering the tablet or formulation in an effective amount oramounts known in the art.

The formulation can be characterized as highly drug loaded with theferric citrate present in the formulation at values of greater thanapproximately 65% by weight of the formulation, greater thanapproximately 70% by weight of the formulation and as high asapproximately 92% of the formulation. Intermediate values such asapproximately 80% by weight ferric citrate, approximately 85% by weightferric citrate and approximately 90% by weight ferric citrate also canbe used in the ferric citrate formulation. The characteristics of thetablet produced at these highly loaded weight percentages are controlledby variables such as binder, binder amount, disintegrant, disintegrantamount, formulation method used (e.g., granulation, direct compression),tableting parameters, etc. Thus if a tablet is made and it has a slightamount of lamination or capping, by varying one or more of the abovevariables the lamination or capping can be corrected.

In various embodiments, the tablet formulation contains one or morecomponents selected from among one or more binders, one or morelubricants, and one or more disintegrants.

The binder can be any binder known in the art. Without limitation,examples of the binder can include one or more of hydroxypropylcellulose (HPC), hydroxypropylmethyl cellulose (HPMC), sodium alginate,alginic acid, guar gum, acacia gum, xanthan gum, carbolpol, cellulosegum (carboxy methyl cellulose), ethyl cellulose, maltodextrin, PVP/VA,povidone, microcrystalline cellulose, starch (partially or fullypregelatinized starch) and methyl cellulose. The maltodextrin, PVP/VA,and methyl cellulose function as immediate release binders when used inthe ferric citrate formulations.

It also should be understood that combinations of binders can be used tocontrol and vary the effect of the binder. For example, a binder systemcan be made up of hydroxypropyl cellulose and polyvinyl pyrrolidone(povidone) with or without microcrystalline cellulose. One or both ofthe hydroxypropyl cellulose and povidone can be replaced withpregelatinized starch.

In various aspects, the tablet can include a lubricant. As an example ofa lubricant for the ferric citrate formulations, magnesium stearate,calcium stearate, sodium stearyl fumarate and combinations can be used.Other suitable lubricants include one or more of polyethylene glycol(molecular weight above 3350), sodium lauryl sulfate, talc, mineral oil,leucine, and poloxamer.

In various aspects, the tablet can include a disintegrant. Thedisintegrant can be included in the formulation. The disintegrant can bethe same as or different from the binder. By way of example and notlimitation, microcrystalline cellulose has both binder and disintegrantproperties and microcrystalline cellulose can be use as the solebinder/disintegrant in the formulation. Examples of other suitabledisintegrants include croscarmellose sodium, crospovidone, sodium starchglycolate, and starch.

The binder can be present in the formulation in an amount ranging fromapproximately 4.5% by weight to approximately 30% by weight. Thedisintegrant can be present in the formulation in an amount ranging fromapproximately 1.5% by weight to approximately 15% by weight. In variousembodiments, some non-starch disintegrants are often used at lowerranges, e.g., as low as 0.25% and thus the disintegrant present in theformulation can be as low as 0.25% in some conditions.

The lubricant can be present in the formulation in an amount rangingfrom approximately 0.5% by weight to approximately 3% by weight. Itshould be understood that some components, such as microcrystallinecellulose, can function with both disintegrant and binder properties.

The weight of individual tablets can depend upon the final dosage to beproduced; e.g. 125 mg, 250 mg, 500 mg, 667 mg, 750 mg and 1,000 mg offerric citrate.

In various embodiments, tablets are coated to a weight gain ofapproximately 2% to 5% using an Opadry® suspension or equivalent in aperforated pan coater. As noted above, calcium stearate and Opadry®purple can be replaced with or used with a different lubricant orcoating system, respectively.

Tablets Having High Surface Area Per Unit Mass

In one variation, the disclosed tablets are made from granules having asignificantly higher mean surface area per unit mass than previousferric citrate formulations. It has been discovered that the increasedsurface area per unit volume results in immediate release dissolutiontimes (greater than 80% at 60 minutes after administration as determinedby United States Pharmacopeia (USP) test <711>, described in UnitedStates Pharmacopeia Compendium of Standards, USP 30 NF 25, Vol. 1 p.276-284 (2007), which is incorporated herein by reference in itsentirety). Without wishing to be limited to a specific theory or mode ofaction, the increased granular surface area of granules in the tabletresults in an increased amount of ferric citrate exposed to the solvent.The immediate release dissolution times are significantly reduced in areduced tablet size.

In additional variations, the tablets disclosed herein can be designedto have a mean granule particle surface area to mass ratio equal to orgreater than 1 square meter per gram. In further variations, the tablethas a mean granule particle surface area to mass ratio equal to orgreater than 2 square meters per gram. In further variations, theformulation has a mean granule particle surface area to mass ratio equalto or greater than 4 square meters per gram. In further variations, theformulation has a mean granule particle surface area to mass ratio equalto or greater than 6 square meters per gram. In further variations, theformulation has a mean granule particle surface area to mass ratio equalto or greater than 8 square meters per gram. In further variations, theformulation has a mean granule particle surface area to mass ratio equalto or greater than 10 square meters per gram. In further variations, theformulation has a mean granule particle surface area to mass ratio equalto or greater than 15 square meters per gram. In further variations, theformulation has a mean granule particle surface area to mass ratio equalto or greater than 20 square meters per gram. In further variations, theformulation has a mean granule particle surface area to mass ratio equalto or greater than 30 square meters per gram. In further variations, theformulation has a mean granule particle surface area to mass ratio equalto or greater than 40 square meters per gram. In further variations, theformulation has a mean granule particle surface area to mass ratio equalto or greater than 50 square meters per gram. The increased surface areaper particle in a tablet resulted in a significantly increaseddissolution rate.

In other variations, the tablets have reduced water content. In oneembodiment, the granulation water content as measured by LOD % is lessthan 20%. In another embodiment, the granulation water content asmeasured by LOD % is less than 19%. In another embodiment, thegranulation water content as measured by LOD % is less than 18%. Inanother embodiment, the granulation water content as measured by LOD %is less than 17%. In another embodiment, the granulation water contentas measured by LOD % is less than 16%. In another embodiment, thegranulation water content as measured by LOD % is less than 15%. Inanother embodiment, the granulation water content as measured by LOD %is less than 14%. In another embodiment, the granulation water contentas measured by LOD % is less than 13%. In another embodiment, thegranulation water content as measured by LOD % is less than 12%. Inanother embodiment, the granulation water content as measured by LOD %is less than 11%. In another embodiment, the granulation water contentas measured by LOD % is less than 10%. In another embodiment, thegranulation water content as measured by LOD % is less than 9%. Inanother embodiment, the granulation water content as measured by LOD %is less than 8%. In another embodiment, the granulation water content asmeasured by LOD % is less than 7%. In another embodiment, thegranulation water content as measured by LOD % is less than 6%. Inanother embodiment, the granulation water content as measured by LOD %is less than 5%.

As will be understood to those of skill in the art, in variousembodiments LOD is a method of thermogravimetric moisture determination:In thermogravimetric processes the moisture of a material includessubstances that volatilize during warming, and therefore contribute tothe material's loss of mass. Alongside water this may also includealcohol or decomposition products. When using thermogravimetricmeasurement methods (drying using infrared, halogen, microwaves orovens) no distinction is made between water and other volatilecomponents.

Friability

Friability generally measures the mechanical strength of tablets. Duringthe process of coating, transportation, packing, and other processes,tablets can lose weight. To measure the weight loss the samples arecounted and weighed.

In various embodiments, a friability test is performed as described inUnited States Pharmacopeia Compendium of Standards (2007), which isincorporated herein by reference in its entirety.

Chapter <1216> of the United States Pharmacopeia Compendium of Standards(2007) regarding tablet friability is recited below:

This general information chapter has been harmonized with thecorresponding texts of the European Pharmacopoeia and the JapanesePharmacopoeia. The harmonized texts of these three pharmacopeias aretherefore interchangeable, and the methods of the European Pharmacopoeiaand/or the Japanese Pharmacopoeia may be used for demonstration ofcompliance instead of the present United States Pharmacopeia generalinformation chapter method. These pharmacopeias have undertaken not tomake any unilateral change to this harmonized chapter.

This chapter provides guidelines for the friability determination ofcompressed, uncoated tablets. The test procedure presented in thischapter is generally applicable to most compressed tablets. Measurementof tablet friability supplements other physical strength measurements,such as tablet breaking force.

Use a drum (the apparatus meeting these specifications is available fromlaboratory supply houses such as VanKel Technology Group, 13000 WestonParkway, Cary, N.C. 27513, or from Erweka Instruments, Inc., 56 QuirkRoad, Milford, Conn. 06460), with an internal diameter between 283 and291 mm and a depth between 36 and 40 mm, of transparent syntheticpolymer with polished internal surfaces, and subject to minimum staticbuild-up (see FIG. 1 for a typical apparatus). One side of the drum isremovable. The tablets arc tumbled at each turn of the drum by a curvedprojection with an inside radius between 75.5 and 85.5 mm that extendsfrom the middle of the drum to the outer wall. The outer diameter of thecentral ring is between 24.5 and 25.5 mm. The drum is attached to thehorizontal axis of a device that rotates at 25±1 rpm. Thus, at each turnthe tablets roll or slide and fall onto the drum wall or onto eachother. For tablets with a unit weight equal to or less than 650 mg, takea sample of whole tablets corresponding as near as possible to 6.5 g.For tablets with a unit weight of more than 650 mg, take a sample of 10whole tablets. The tablets should be carefully dedusted prior totesting. Accurately weigh the tablet sample, and place the tablets inthe drum. Rotate the drum 100 times, and remove the tablets. Remove anyloose dust from the tablets as before, and accurately weigh.

Generally, the test is run once. If obviously cracked, cleaved. orbroken tablets are present in the tablet sample after tumbling, thesample fails the test. If the results are difficult to interpret or ifthe weight loss is greater than the targeted value, the test should berepeated twice and the mean of the three tests determined. A maximummean weight loss from the three samples of not more than 1.0% isconsidered acceptable for most products.

If tablet size or shape causes irregular tumbling, adjust the drum baseso that the base forms an angle of about 10° with the horizontal and thetablets no longer bind together when lying next to each other, whichprevents them from falling freely.

Effervescent tablets and chewable tablets may have differentspecifications as tar as friability is concerned. In the case ofhygroscopic tablets, an appropriate humidity-controlled environment isrequired for testing.

Drums with dual scooping projections, or an apparatus with more than onedrum, for the running of multiple samples at one time, are alsopermitted.

Method of Making Tablets

In one tableting method, the tablets can be prepared in three steps.First, granules of ferric citrate and binder are formed. Second, alubricant is added to the formulation before tableting. Third, thetablet is dried after an optional coating step.

Granulation

Ferric citrate, such as pharmaceutical grade ferric citrate described,for example, in U.S. Pat. No. 6,903,235 B2, can be granulated by anymethod known in the art. Exemplary methods of granulation include fluidbed granulation, high shear granulation and direct compressiongranulation.

In embodiments in which the moisture of the formulation was brought tothe level above 25% LOD at any point resulted in a substantially lowersurface area per gram of particle. This can be accomplished, forexample, by limiting the quantity of water introduced, or by air blowingand monitoring the amount of water in a formulation.

To increase the surface area to mass ratio of ferric citrate particlesto greater than 1 square meter per gram, or in other embodiments greaterthan 10 square meter per gram, the moisture content of the granules ismaintained below 25% LOD throughout formation of granules. In certainvariations, the moisture content of the granules is maintained at below24% LOD, 23% LOD, 22% LOD, 21% LOD, or 20% LOD, throughout formation ofgranules.

Without wishing to be held to a particular mechanism or mode of action,it is hypothesized that keeping the amount of water below 25% LOD duringgranulation maintains granules with a high surface area per mass ratio.The addition of water in higher amounts at any time during thegranulation process results in formation of larger granules with a lowermean surface area to mass ratio. The lower surface area to mass reducesthe dissolution rate below the rate for an immediate releaseformulation. The measured lower mean surface area to mass ratio ofgranules results in slower dissolution and release characteristics.

In various embodiments, it has been observed that the reduced surfacearea to weight ratio of the ferric citrate formulation is irreversibleafter addition of moisture at above 25% LOD. Accordingly, the percentwater is kept below 25% during granulation in various embodiments.

Blending

In various embodiments, one or more lubricants can be blended with thegranules. In various embodiments, a non-limiting list of lubricantsincludes stearates such as calcium stearate and magnesium stearate,sodium stearyl fumarate, stearic acid, talc, polyethylene glycol,hydrogenated vegetable oils, aluminum stearate, sodium benzoate, sodiumacetate, sodium chloride, leucine, Carbowax, and magnesium laurylsulfate. Certain starches, such as Starch 1500, can also be consideredlubricants, as they have some lubricant properties when used in directcompression application. Any lubricant known in the art can be used,including any of those disclosed in the Handbook of PharmaceuticalExcipients fifth edition, incorporated herein by reference in itsentirety. Multiple lubricants can be combined.

In certain embodiments, a greater quantity of lubricant than isordinarily used in the art can be used. It has been discovered thatsurprisingly, the quantity of lubricant must be higher than recommendedor understood in the industry to reduce the quantity of sticking in theferric citrate tablets.

In certain variations, a combination of magnesium or calcium stearateand sodium stearyl fumarate is used as a lubricant. In furtherembodiments, the lubricant is a combination of calcium stearate andsodium stearyl fumarate. In various embodiments, a greater quantity ofcalcium stearate than is recommended in the art can be used. Asdescribed in the Handbook of Pharmaceutical Excipients fifth edition,the recommended quantity of calcium stearate is a maximum of 1.0% w/w.In one embodiment, the quantity of calcium stearate is equal to orgreater than 2.0% w/w. In another embodiment, the quantity of calciumstearate is equal to or greater than 2.2% w/w. In another embodiment,the quantity of calcium stearate is equal to or greater than 2.4% w/w.

Likewise, in various embodiments, a greater quantity of sodium stearylfumarate than the recommended 0.5-2.0% w/w concentration can be used. Inone embodiment, the quantity of sodium stearyl fumarate is greater thanor equal to 2.1% w/w. In another embodiment, the quantity of sodiumstearyl fumarate is greater than or equal to 2.2% w/w. In anotherembodiment, the quantity of sodium stearyl fumarate is greater than orequal to 2.3% w/w. In another embodiment, the quantity of sodium stearylfumarate is greater than or equal to 2.4% w/w. In another embodiment,the quantity of sodium stearyl fumarate is greater than or equal to 2.5%w/w. In another embodiment, the quantity of sodium stearyl fumarate isgreater than or equal to 2.6% w/w. In another embodiment, the quantityof sodium stearyl fumarate is greater than or equal to 2.7% w/w.

Post-Tableting Drying

A drying step can be performed after tableting. In the absence of dryingthe tablet after tableting, it was discovered that the dissolution rateof tablets increased over time. Drying maintained the immediate releasecharacteristics of the ferric citrate tablets as disclosed herein.Without being limited to a specific mechanism or mode of action, it isbelieved that granule size increases due to the presence of residualwater, and the drying step maintains the large surface area per unitweight of the original granules.

In one embodiment, the final granulation water content as measured byLOD % is less than 20%. In another embodiment, the final granulationwater content as measured by LOD % is less than 19%. In anotherembodiment, the final granulation water content as measured by LOD % isless than 18%. In another embodiment, the final granulation watercontent as measured by LOD % is less than 17%. In another embodiment,the final granulation water content as measured by LOD % is less than16%. In another embodiment, the final granulation water content asmeasured by LOD % is less than 15%. In another embodiment, the finalgranulation water content as measured by LOD % is less than 14%. Inanother embodiment, the final granulation water content as measured byLOD % is less than 13%. In another embodiment, the final granulationwater content as measured by LOD % is less than 12%. In anotherembodiment, the final granulation water content as measured by LOD % isless than 11%. In another embodiment, the final granulation watercontent as measured by LOD % is less than 10%. In another embodiment,the final granulation water content as measured by LOD % is less than9%. In another embodiment, the final granulation water content asmeasured by LOD % is less than 8%. In another embodiment, the finalgranulation water content as measured by LOD % is less than 7%. Inanother embodiment, the final granulation water content as measured byLOD % is less than 6%. In another embodiment, the final granulationwater content as measured by LOD % is less than 5%.

EXAMPLES

The following examples describe the preparation and properties ofvarious dosage forms and methods described herein. It will be apparentto those skilled in the art that many modifications, both to materialsand methods, can be practiced without departing from the scope of thedisclosure.

Example 1

The following exemplary formulations and formulation techniques forferric citrate provide data showing characteristics for the formulationsor tablets, including data such as dissolution, disintegration, andfriability.

The sources for some of the materials included: ferric citrate fromBiovectra; silicified microcrystalline cellulose (Prosolv SMCC 50 andProsolv SMCC HD90 which is composed of microcrystalline cellulose, NFand colloidal silicon dioxide, NF) from JRS Pharma; pregelatinizedstarch, NF (Starch 1500) from Colorcon; Povidone, NF (Plasdone K-29/32)from ISP; hydroxypropyl cellulose, NF (Klucel EF) from Hercules;croscarmellose sodium, NF (Ac-Di-Sol SD-711) from FMC Biopolymer; andmagnesium stearate, NF from Mallinckrodt.

The equipment used for the formulations included: FLM1 fluid bed fromVector Corporation of Marion, Iowa; Comil conical mill from QuadroEngineering of Millburn, N.J.; GMX high shear granulator 4 L bowl fromVector Corporation of Marion, Iowa; 2 qt V-blender from Patterson Kelleyof East Stroudsburg, Pa.; XL100 Pro tablet press from Korsch of SouthEaston, Mass.; capsule-shaped tooling from Elizabeth Carbide ofLexington, N.C.; and Sonic sifter separator from Advantech Manufacturingof New Berlin, Wis.

The equipment used for the analytical testing of the formulationsincluded: 8M Tablet Tester (hardness tester) from Dr. Schleuniger ofManchester, N.H.; Friabilator from VanKel of Palo Alto, Calif.; Flodexfrom Hanson Research of Chatsworth, Calif.; Bathless DisintegrationSystem, Model 3106 and Bathless Dissolution System, Evolution 6100 fromDistek of North Brunswick, N.J.; and Model 8453 UV-Vis from Agilent ofSanta Clara, Calif.

High Shear Granulation

A series of experiments were conducted to determine the ability to use ahigh shear granulator to make a tablet blend having suitablecharacteristics. Formulations 1-3 are shown below in Tables 1-3.

TABLE 1 (Formulation 1) Component mg/tablet % w/w Milled ferric citrate1190.3 75.0 Silicified microcrystalline 238.1 15.0 cellulose (ProsolvSMCC 50) Croscarmellose sodium 47.6 3.0 Hydroxypropyl cellulose 95.2 6.0Magnesium stearate 15.9 1.0 Total 1587.0 100.0

TABLE 2 (Formulation 2) Component mg/tablet % w/w Milled ferric citrate1190.4 60.0 Silicified microcrystalline 595.2 30.0 cellulose (ProsolvSMCC 50) Croscarmellose sodium 59.5 3.0 Hydroxypropyl cellulose 119.06.0 Magnesium stearate 19.8 1.0 Total 1984.0 100.0

TABLE 3 (Formulation 3) Component mg/tablet % w/w Milled ferric citrate1190.3 69.0 Silicified microcrystalline 258.8 15.0 cellulose (ProsolvSMCC 50) Croscarmellose sodium 86.3 5.0 Hydroxypropyl cellulose 172.510.0 Magnesium stearate 17.3 1.0 Total 1725.0 100.0

The manufacturing procedure for the Formulations 1-3 was as follows.

Milled ferric citrate, hydroxypropyl cellulose, silicifiedmicrocrystalline cellulose, and croscarmellose sodium were mixed for 2minutes at 500 rpm in a GMX high shear granulator 4 L bowl. Deionizedwater was added at an approximate rate of 18 g/min over 10 minutes,while mixing at a rate of 900 rpm with a chopper speed of 1500 rpm. Thefinal (peak) moisture content was measured to be 24.3%, 23.8%, and24.4%, respectively. The granules were dried in an FLM1 fluid bed for5-8 minutes at an inlet temperature of 65° C. The moisture content afterdrying was measured to be 14.3%, 15.5%, and 15.9%, respectively. Thegranules were screened through a 16 mesh hand-screen, then through a 25mesh hand screen to remove over-sized granules and clumps. The magnesiumstearate was screened through a 25 mesh hand-screen. Granules andmagnesium stearate were blended for 2 minutes in a 2 quart v-blender.Tableting was performed on a Korsch tablet press with capsule shapedtooling.

It was found that the resulting tablet blends demonstrated poor flowthrough the hopper due to the irregular particle shape of the granules.Nonetheless, excellent tablets were made using the tableting equipment.

Example 2

Another series of experiments were conducted to determine whether atablet could be formulated using a fluid bed granulation process:

TABLE 4 (Formulations 4 and 5) Component mg/tablet % w/w Milled ferriccitrate 1190.7 90.0 Pregelatinized starch 119.1 9.0 Magnesium stearate13.2 1.0 Total 1323.0 100.0

The manufacturing procedure for Formulations 4 and 5 depicted in Table 4are provided below as follows:

Milled ferric citrate was added to an FLM1 fluid bed granulator. ForFormulation 4, pregelatinized starch was added as a 10% w/w solution ata spray rate that increased from 24 g/min to 52 g/min over the durationof the run. [Inlet Temp=64-77° C.; Product Temp=25-35° C.; ProcessAir=29-35 CFM]. The final (peak) moisture content was measured to be32.5%.

For Formulation 5, pregelatinized starch was added as a 10% w/w solutionat an average spray rate of 40.8 g/min. [Inlet Temp=69-75° C.; ProductTemp=25-35° C.; Process Air=24-38 CFM]. The final (peak) moisturecontent was measured to be 30.0%.

The granules were dried for 7-10 minutes at an inlet temperature of 65°C. The moisture content after drying was measured to be 15.5% and 16.7%.Granules were milled through a Comil equipped with a 45R screen andsquare impeller at 1500 rpm. The magnesium stearate was screened througha 25 mesh hand-screen. Granules and magnesium stearate were blended fortwo minutes in a two quart V-blended. Tableting was performed on aKorsch tablet press with capsule shaped tooling.

The primary difference between the tablets of Formulations 4 and 5 wasthe disintegration time. The tablets of Formulation 5 had a slowerdisintegration time than the tablets of Formulation 4. These prototypeshad no flow problems during tableting.

The powder properties of Formulations 1-5 were characterized as shown inTables 5 and 6. All blends had excellent flow properties as measured bythe Flodex.

TABLE 5 Powder Characterization of High Shear Blends MeasurementFormulation 1 Formulation 2 Formulation 3 Bulk density 0.772 g/mL 0.618g/mL 0.679 g/mL Flodex 4 5 10

TABLE 6 Powder Characterization of Fluid Bed Blends MeasurementFormulation 4 Formulation 5 Bulk density 0.647 g/mL 0.578 g/mL Flodex 44

Experimental formulations of Formulations 1 and 5 were examined byScanning Electron Microscopy (SEM) and both samples had a similarparticle size range. While the particles of Formulation 1 appeared tohave a bimodal distribution, both samples had distinct particlemorphologies. Formulation 1, which was prepared by high sheargranulation, had more sharp, oblong particles. Formulation 5, preparedby fluid bed granulation, had more soft, round particles. Thisdifference is believed to have an impact on the flow properties observedduring tableting.

The tablet properties of Formulations 1-5 were characterized as shown inTable 7 and Table 8. Compaction profiles were made of each formulation,graphically presented in FIG. 2 (hardness), FIG. 3 (friability), andFIG. 4 (disintegration). Characterization data is presented only of thetablets prepared at the highest compaction force. Compression force ismeasured in kilo Newtons. Dissolution results are graphically presentedin FIG. 5 for Formulations 1 and 3-5.

For the hardness testing, the tablets were tested according to USP<1217> for hardness/breaking strength. For the friability testing, thetablets were tested following USP <1216> for friability. For thedisintegration testing, six tablets were tested using a disintegrationapparatus in deionized water at 37° C. For the dissolution testing, sixtablets were tested for dissolution properties according to theconditions listed below. Tablet dissolution results were scaled toreport 100% dissolution as a 1000 mg dose, correcting for actual averagetablet weight, as needed.

Dissolution Conditions:

Dissolution Instrument: Distek Evolution 6100

Medium: pH 4.0 McIlvaine buffer

Apparatus USP: Apparatus II (paddle method); 100 rpm

Temperature: 37° C.±0.5° C.

Time: Samples taken at 5, 15, 30, and 60 minutes

UV-Vis Instrument: Agilent 8453 UV-Vis; 360 nm with 600 nm backgroundcorrection.

TABLE 7 Characterization of High Shear Experiments (Formulations 1-3)Formulation Measurement Formulation 1 Formulation 2 3 Weight Average1580.8 mg Average 1485.6 mg Average variation (0.5% RSD) (0.4% RSD)1518.4 mg (0.7% RSD) Thickness Average 8.59 mm Average 8.37 mm Average(0.2% RSD) (0.2% RSD) 8.69 mm (0.4% RSD) Hardness 18.1 kp 19.5 kp 21.5kp (2.6% RSD) (2.3% RSD) (3.8% RSD) Friability 0.19% 0.22% 0.26%Disintegration Average 5.8 Average 19.8 Average 3.0 minutes minutesminutes Dissolution 48.2% in 60 — 49.7% in 60 minutes minutes

TABLE 8 Tablet Characterization of Fluid Bed Experiments (Examples 4 and5) Measurement Formulation 4 Formulation 5 Weight variation Average1286.5 mg Average 1313.2 mg (0.3% RSD) (0.4% RSD) Thickness Average 7.18mm Average 7.24 mm (0.2% RSD) (0.2% RSD) Hardness Average 19.3 kp 20.5kp (3.2% RSD) (7.4% RSD) Friability 0.20% 0.23% Disintegration Average7.7 minutes Average 36.3 minutes Dissolution 50.4% in 60 minutes 42.5%in 60 minutes

For the high shear prototypes (Formulations 1-3) incorporation ofincreased silicified microcrystalline cellulose (Formulation 1 andFormulation 2) improved compactibility, as shown by reduced compressionforces required to achieve equivalent hardness. Also, incorporation ofincreased hydroxypropyl cellulose (Formulations 1, 2, and 3) improvedcompactibility, as shown by reduced compression forces required toachieve equivalent hardness.

Example 3

Additional development was conducted to achieve a balance betweendissolution profile and acceptable tablet properties. The fluid bedgranulation spray rate was varied step-wise using pregelatinized starch,which showed that in-process moisture content plays a role indissolution profile and tablet properties.

Fluid Bed Granulation with Starch

Batches of Formulations 6-11 shown in Tables 9 and 10 were preparedusing pregelatinized starch with target batch sizes of 1.0 kg.

TABLE 9 Formulation Formulations 6-8 Component mg/tablet % w/w Milledferric citrate 1190.7 90.0 Pregelatinized starch 119.1 9.0 Magnesiumstearate 13.2 1.0 Total 1323.0 100.0

TABLE 10 Formulation Formulations 9-11 Component mg/tablet % w/w Milledferric citrate 1190.7 80.9 Pregelatinized starch 119.1 8.1 Silicifiedmicrocrystalline cellulose 147.2 10.0 Magnesium stearate 13.2 1.0 Total1470.2 100.0

Formulations 6-11 were manufactured as follows:

Milled ferric citrate was added to an FLM1 fluid bed granulator.Pregelatinized starch was added as a 10% w/w solution using thegranulation and drying parameters in Table 11. All batches were dried atan inlet temperature of 65° C.

TABLE 11 Granulation Parameters Formulation 6 Formulations FormulationsParameter and 9 7 and 10 8 and 11 Spray rate 24.0 g/min 32.5 g/min 37.5g/min Inlet temp 69-79° C. 72-75° C. 69-76° C. Product temp 26-35° C.26-36° C. 26-35° C. Process air 31-36 CFM 32-38 CFM 36-39 CFM Final(peak) moisture 17.3% 23.4% 25.7% Moisture after drying 14.8% 16.1%17.5% Drying time 2 minutes 5 minutes 7 minutes

Granules from Formulations 6, 7, 9 and 10 were screened through a 20mesh hand-screen. Granules from Formulations 8 and 11 were milledthrough a Comil equipped with a 45R screen and square impeller at 1500rpm, then screened through a 20 mesh hand-screen.

Two blends were prepared from each granulation. In the first blend, themagnesium stearate was screened through a 25 mesh hand-screen. Granulesand magnesium stearate were blended for two minutes in a two quartV-blender. In the second blend, the magnesium stearate was screenedthrough a 25 mesh hand-screen. Granules, silicified microcrystallinecellulose, and magnesium stearate were blended for two minutes in a twoquart V-blender.

Tableting was performed on a Korsch tablet press with capsule shapedtooling on several of the prepared blends.

The resulting tablets of Formulations 6 and 9 had flow properties withHausner ratio values equal to or less than 1.25 and/or Carr index valuesequal to or less than 25. In various embodiments, the Hauser ratio isequal to or less than 1.20. In further embodiments, the Hauser ratio isequal to or less than 1.20. In various embodiments, the Carr index isless than 25. In further embodiments, the Carr index is equal to or lessthan 20.

Excellent flow: Hausner ratio values about or less than 1.20 and Carrindex values less than 20 showed evidence that additional lubricationwas needed to achieve better tableting results. The resulting tablets ofFormulations 7, 8, 10 and 11 had excellent flow properties and madesuccessful tablets.

The powder properties of Formulations 6-11 were characterized as shownin Table 12. Formulations 7, 8, 10 and 11 have flow properties withHauser ratios equal to or less than 1.20 and Carr index values less than20 as measured by the Flodex, presumably due to the higher spray ratesof those experiments. The bulk density of the starch granulationexperiments increased as the spray rate increased.

TABLE 12 Powder Characterization of Fluid Bed Experiments Formulations 6Formulations 7 Formulations 8 Measurement and 9 and 10 and 11 Bulkdensity 0.475 g/mL 0.531 g/mL 0.698 g/mL Flodex 7 4 4

The tablet properties of Formulations 6-8 and 11 were characterized asshown in Table 13 and 14. Compaction profiles were made for eachformulation and are graphically presented in FIG. 6 (hardness), FIG. 7(friability) and FIG. 8 (disintegration). Characterization data ispresented only of the tablets prepared at the highest compaction force.Dissolution results are graphically presented in FIG. 9 for Formulations6-8 and 11.

TABLE 13 Tablet Characterization of Fluid Bed Formulations 6 and 7Measurement Formulation 6 Formulation 7 Weight Average 1126.9 mg (0.4%Average 1272.8 mg (0.4% variation RSD) RSD) Thickness Average 7.74 mmAverage 8.00 mm (0.2% RSD) (0.5% RSD) Hardness Average 11.2 kp 27.2 kp(8.9% RSD) (28.7% RSD) Friability 2.23% 0.36% Disintegration Average 1.8minutes Average 3.9 minutes Dissolution 99.9% in 60 minutes 95.7% in 60minutes

TABLE 14 Tablet Characterization of Fluid Bed Formulations 8 and 11Measurement Formulation 8 Formulation 11 Weight variation Average 1332.0mg Average 1497.7 mg (0.3% RSD) (0.3% RSD) Thickness Average 7.94 mmAverage 8.72 mm (0.1% RSD) (0.1% RSD) Hardness Average 21.1 kp (2.8%RSD) 26.1 kp (2.9% RSD) Friability 0.28% 0.15% Disintegration Average11.7 minutes Average 8.3 minutes Dissolution 55.8% in 60 minutes 65.6%in 60 minutes

Milled ferric citrate and croscarmellose sodium were added to an FLM1fluid bed. Povidone was added as a 30% w/w solution (Formulation 12) and20% w/w solution (Formulation 13) using the granulation and dryingparameters in Table 15 to make granules. No drying was required.

TABLE 15 Granulation Parameters Parameter Formulation 12 Formulation 13Spray rate 22.9 g/min 30.0 g/min Inlet temp 55-60° C. 52-58° C. Producttemp 31-37° C. 22-30° C. Process air 31-36 CFM 35-38 CFM Final (peak)moisture 13.0% 17.3%

Granules were screened through a 20 mesh hand-screen. The magnesiumstearate was screened through a 25 mesh hand-screen. Granules andmagnesium stearate were blended for two minutes in a two quartV-blender.

Tableting was performed on a Korsch tablet press. During the tabletingprocess, there was excessive sticking to the tooling. This sticking wasbelieved to be addressable by use of different tooling or by varying thetableting parameters.

Example 4

Additional examples were formulated and analyzed. A summary of theresults are provided below in Tables 16 and 17. Table 16 provides asummary of results for Formulations 14-20 using direct compression ofthe formulations. Table 17 provides a summary of results forFormulations 21-29 using fluid bed granulation. These variousformulations showed a variety of ranges of properties that could beuseful depending upon the application, e.g., immediate release, extendedrelease, and delayed release, with a minor amount of additionalexperimentation required for some of the formulations to ensure thatsuitable tablets are formed.

TABLE 16 Qualitative Results for Direct Compression FormulationsExperiment Dose Reference Target Formulation Summary Results andObservations Formulation 667 mg 91.9% Ferric Citrate, Tablets had somelamination, 14 7.3% Prosolv SMCC 50, achieved 12.5 kp average 0.8%Magnesium Stearate hardness Formulation 667 mg 91.9% Ferric Citrate,Friability equal to or less than 15 7.3% Prosolv HD 90, 1.0% w/w. 0.8%Magnesium Stearate Formulation 667 mg 87.0% Ferric Citrate, Friabilityequal to or less than 16 7.3% Prosolv SMCC 50, 1.0% w/w. 4.9% PovidoneK-29/32, 0.8% Magnesium Stearate Formulation 500 mg 90.7% FerricCitrate, Tablets showed capping and 17 8.5% Prosolv HD 90, laminationaddressable with 0.8% Magnesium Stearate additional binder or varyingthe tableting parameters Formulation 500 mg 90.7% Ferric Citrate,Tablets showed capping and 18 8.0% Prosolv HD 90, lamination addressablewith 0.5% Povidone K-29/32, additional binder or varying the 0.8%Magnesium Stearate tableting parameters; long disintegration timesFormulation 500 mg 88.0% Ferric Citrate, Tablets showed capping and 197.0% Avicel PH 200, lamination addressable with 2.7% Povidone K-29/32,additional binder or varying the 1.5% Crospovidone XL, tabletingparameters; 0.8% Magnesium Stearate disintegration time reduced to 1-3minutes suitable for immediate release applications Formulation 500 mg87.0% Ferric Citrate, Tablets showed reduced lamination 20 7.0% AvicelPH 200, that was addressable with 3.7% Povidone K-29/32, additionalbinder or varying the 1.5% Crospovidone XL, tableting parameters, 0.8%Magnesium Stearate disintegration time 3-5 minutes suitable forimmediate release applications

TABLE 17 Qualitative Results for Fluid Bed Granulation FormulationsExperiment Dose Reference Target Formulation Summary Results andObservations Formulation 500 mg 90.0% Ferric Citrate, Friability equalto or less than 21 2.0% Povidone K-29/32, 1.0% w/w. 2.0% Starch 1500,5.2% Avicel PH 102, 0.8% Magnesium Stearate Formulation 500 mg 90.0%Ferric Citrate, Acceptable tablet properties with 22 4.0% Starch 1500,additional development work 5.2% Avicel PH 102, needed for tabletintegrity 0.8% Magnesium Stearate Formulation 500 mg 90.0% FerricCitrate, Tablets had disintegration 23 9.0% Starch 1500, more than 15minutes. 1.0% Magnesium Stearate Formulation 500 mg 90.0% FerricCitrate, Tablets had disintegration 24 4.0% Starch 1500, more than 15minutes. 5.2% Avicel PH 102, 0.8% Magnesium Stearate Formulation 500 mg80.0% Ferric Citrate, Tablets had disintegration 25 8.0% Starch 1500,more than 15 minutes. 11.0% Avicel PH 200, 1.0% Magnesium StearateFormulation 500 mg 90.0% Ferric Citrate, Tablets had disintegration 269.0% Starch 1500, more than 15 minutes. 1.0% Magnesium StearateFormulation 500 mg 85.0% Ferric Citrate, Tablets had disintegration 278.5% Starch 1500, more than 15 minutes. 5.5% Avicel PH 200, 1.0%Magnesium Stearate Formulation 1000 mg  84.9% Ferric Citrate,Granulation very dense 28 5.6% Starch 1500, 8.6% Avicel PH 200, 1.0%Magnesium Stearate Formulation 1000 mg  89.5% Ferric Citrate, Acceptabletablet properties with 29 5.9% Starch 1500, tableting and coatingsuccessful 3.6% Avicel PH 200, 1.0% Magnesium Stearate

Example 5

Tables 18a and 18b provide Formulations 30 and 31 for an exemplaryferric citrate drug product.

TABLE 18a Formulation 30 for a Ferric Citrate Drug Product MaterialTheoretical Description kg/Batch % w/w Ferric Citrate 14.89 87.6Pregelatinized Starch 1.70 10.0 Calcium Stearate 0.406 2.4 PurifiedWater 15.30* N/A** Core Tablet Total 17.00 100.0 Opadry Purple 03K1000000.51 15.0 Purified Water 2.89* 85.0** Coated Tablet Total 17.5 100.0*Purified water is removed during the drying phase.

TABLE 18b Formulation 31 for a Ferric Citrate Drug Product MaterialTheoretical Description Kg/Batch % w/w Ferric Citrate 14.87 85.0Silicified Microcrystalline 0.70 4.0 Cellulose Pregelatinized Starch1.58 9.0 Calcium Stearate 0.35 2.0 Purified Water 14.18 N/A* Core TabletTotal 17.5 100.0 Opadry Purple 03K100000 0.51* 15.0 Purified Water 2.89*85.0** Coated Tablet Total 18.0 100.0

Table 19 provides a proposed ferric citrate drug product formulationthat can be used in the manufacturing process described below.

TABLE 19 Formulation 32 Material Theoretical % w/w to Core % w/w CoatedDescription 100 kg/Lot Tablet Tablet Ferric Citrate 80.0-90.0 80.0-90.076.2-88.2 Pregelatinized  8.0-15.0  8.0-15.0  7.6-14.7 Starch CalciumStearate 2.0-3.0 2.0-3.0 1.9-2.9 Purified Water N/A* N/A* N/A* CoreTablet Total 100.0 100.0 N/A* Opadry Purple 5.3 15.0 2.0-5.0 03K100000Purified Water 30.0* 85.0* N/A* Coated Tablet 35.3 100.0 100.0 Total*Purified water is removed (1) or other binders as listed in the patent(2) or other lubricants as listed in the patent (3) or other coatingsystem as listed in the patent

Example 6

The drug product tablet was produced using fluid bed granulation of thescreened API with a binder suspension of pregelatinized starch,targeting a moisture content after granulation of approximately 13-20%.The granulated active was subsequently blended with screened calciumstearate and the mix compressed to form a tablet core. The tablet wasrobust with friability equal to or less than 1.0% w/w, hardness from8-20 kp, disintegration equal to or less than 15 min, and compressionforce about 3.5-5.0 kN, with a main force 5-20 kN. It will be recognizedthat various embodiments are within the ranges of one or more of each ofthese parameters.

The weight of individual tablets can depend upon the final dosage to beproduced; e.g., 125 mg, 250 mg, 500 mg, 667 mg, 750 mg and 1,000 mg offerric citrate. The process is capable of consistently producing tabletswithin a specification of ±5% of target. The tablet thickness andhardness meet the specified acceptance criteria. The tablets are coatedto a target weight gain of approximately 2% to 5% using an Opadry®suspension or equivalent in a perforated pan coater.

The production results demonstrate the selected formulation and processare capable of producing robust tablets meeting the specified criteria.First, ferric citrate was passed through a screening mill. A granulationdrug binder suspension was then prepared by adding purified water to astainless steel mixing kettle, then adding pregelatinized starch to thepurified water and mixing. Granulated particles were formed by screeningferric citrate through a fluid bed granulator. The pregelatinized starchbinder suspension was sprayed into the fluidized product bed. At thecompletion of binder addition the granulation was dried.

The dried granules were charged into a diffusion mixer. Calcium stearatewas screened and added to the granulation in the diffusion mixer. Thegranules and lubricant were mixed.

The lubricated granules were compressed into tablets. Tablets werecollected in intermediate bulk containers. An aqueous film coatingsuspension was prepared in a stainless steel kettle and mixer. Thetablets were charged into a fully perforated pan coater, and the coatingsuspension was sprayed onto the cascading product bed. Upon completionof the spraying step the tablets were dried. Film coated tablets weredischarged into intermediate bulk containers. The film coated tabletswere packaged in HPDE bottles with desiccant and child resistant foilinduction seal cap.

Example 7

Ferric citrate tablets were formulated as described above. TabletFormulations 33 and 34 are depicted in Tables 20 and 21.

TABLE 20 Formulation 33 % w/w % w/w Material Target Theoretical CoreCoated Description kg/Batch 100 kg/Lot Tablet Tablet Ferric Citrate 14.980.0-90.0 80.0-90.0 76.2-88.2 Pregelatinized 1.7  8.0-15.0  8.0-15.0 7.6-14.7 Starch Calcium Stearate 0.4 1.0-3.0 1.0-3.0 0.9-2.9 (1) OR -Sodium 0.4 2.0-3.0 2.0-3.0 1.9-2.9 Stearyl Fumarate (1) Purified Water15.3*  72.0-135.0* * * Core Tablet 17.0 100.0 100.0 N/A* Total OpadryPurple 0.9 5.3 15.0 2.0-5.0 Purified Water 5.1* 30.0* 85.0* N/A* CoatedTablet 17.5 to 17.9 35.3 100.0 100.0 Total (1) - Either calcium stearateor sodium stearyl fumarate may be used as lubricant *Purified water isremoved

TABLE 21 Formulation 34 % w/w % w/w Material Target Theoretical CoreCoated Description kg/Batch 100 kg/Lot Tablet Tablet Ferric Citrate 14.980.0-90.0 80.0-90.0 76.2-88.2 Pregelatinized 1.6  8.0-12.0  8.0-12.0 7.6-11.5 Starch Silicified 0.7 3.0-5.0 3.0-5.0 2.5-4.5 MacrocrystallineCellulose Calcium Stearate 0.4 1.0-3.0 1.0-3.0 0.9-2.9 (1) OR - Sodium0.4 2.0-3.0 2.0-3.0 1.9-2.9 Stearyl Fumarate (1) Purified Water 15.3* 72.0-135.0* * * Core Tablet 17.6 to 18.0 100.0 100.0 N/A* Total OpadryPurple 0.9 5.3 15.0 2.0-5.0 03K100000 Purified Water 5.1* 30.0* 85.0*N/A* Coated Tablet 17.8 to 18.9 35.3 100.0 100.0 Total (1) - Eithercalcium stearate or sodium stearyl fumarate used as lubricant *Purifiedwater is removed

Example 8

A ferric citrate tablet was made under conditions in which granulationwas conducted by allowing the LOD water % to increase above 25%.

Pharmaceutical grade ferric citrate was added into a fluid bedgranulator. Pregelatinized starch binder suspension (Pregelatinizedstarch+water) was sprayed into the fluidized product bed. The watermoisture level of the formulation was allowed to exceed 25% by LOD (losson drying method).

In embodiments in which the moisture of the formulation was brought tothe level above 25% LOD at any point resulted in a substantially lowersurface area per gram of particle.

Referring to Table 22, the moisture provided during manufacturingincreased above 20% at 120 minutes and increased to 27.89% at 170minutes.

TABLE 22 Granulation Operating Parameters Ex- Rate Pump Inlet InletProduct Atom haust (g/ Speed Air Temp Temp Air LOD Temp Time min) (rpm)(scfm) (° C.) (° C.) (psi) (%) (° C.) 0 — — 145 42 35.8 65.0 11.85 30.610 87.7 30 150 61.6 30.0 65.0 12.82 28.4 20 71.2 30 153 63.5 28.2 65.013.02 26.6 30 76.2 30 153 63.1 27.5 64.7 13.18 25.8 40 77.7 30 144 6327.1 65.1 15.19 25.4 50 75.9 30 146 63.1 27.0 65.1 15.7.0 25.3 60 79.630 147 63.0 26.8 65.1 15.74 25.2 71 80.0 30 144 62.9 26.7 65.1 — 25.1 8083.4 33 149 63.0 26.7 65.1 17.31 25.1 90 90.5 33 151 63.0 26.5 65.118.49 25.0 100 90.4 33 152 63.0 26.5 65.1 18.64 24.9 110 90.5 33 15363.0 26.4 65.1 18.99 24.8 120 90.5 33 150 63.0 26.4 65.1 22.89 24.8 13090.4 33 144 63.0 26.3 65.1 22.47 24.8 141 91.1 33 153 63.0 26.3 65.124.25 24.7 150 90.2 33 152 63.0 26.2 65.1 25.41 24.7 160 91.8 33 15362.9 26.2 65.0 26.03 24.7 170 89.6 33 154 63.0 26.2 65.1 27.89 24.7 18090.7 33 149 63.0 26.2 65.1 27.47 24.7 190 — — 147 63.0 26.4 — 26.76 24.7200 — — 150 63.0 26.8 — 25.00 25.0 210 — — 154 63.1 27.2 — 22.37 25.1220 — — 153 63.1 27.8 — 21.32 25.2 230 — — 149 63.1 29.0 — 18.68 25.7240 — — 153 63.1 30.7 — 17.55 26.5 Final 16.69 LOD

The measured surface area of two samples prepared using the aboveformulation is depicted in Table 23. The surface areas of theformulations were 0.12 m²/g and 0.20 m²/g.

TABLE 23 Sample Sample 1 BET Sample 2 BET Surface Area (m²/g) SurfaceArea (m²/g) Pre- 27.99 32.34 granulation(API + ProSolv) PostGranulation0.12 0.20

The mean surface area per unit mass ratios of the two samples was 0.12and 0.20 m²/g, respectively.

Example 9

A ferric citrate tablet was prepared by keeping granules at an LOD %water concentration less than 25% during granulation.

Pharmaceutical grade ferric citrate was added into a fluid bedgranulator. Pregelatinized starch binder suspension (pregelatinizedstarch+water) was sprayed into the fluidized product bed. With referenceto Table 24, the moisture level of the formulation was maintained atbelow 20% by LOD (loss on drying method) at all times during thespraying process. The surface area of the resulting formulation wasgreater than 10 square meters per gram.

TABLE 24 Spray Ex- Rate Pump Inlet Inlet Product Atom haust Time (g/Speed Air Temp Temp Air Temp LOD (min) min) (rpm) (SCFM) (° C.) (° C.)(psi) (° C.) (%) 0 — — 149 55.4 39.8 — 44.5 12.05 10 86.1 31 153 70.336.0 65.0 39.6 12.44 20 88.2 31 152 70.1 32.0 64.9 35.4 13.01 30 87.9 31146 69.8 30.0 65.1 36.6 13.38 40 90.1 31 153 70.0 28.9 64.8 30.6 13.8050 85.2 31 151 70.0 28.6 65.1 29.8 14.36 60 87.5 31 144 70.0 28.2 65.128.9 15.03 70 89.0 31 153 72.5 28.1 65.1 28.4 16.49 80 87.0 31 145 75.928.4 65.1 28.3 16.34 90 88.7 31 153 78.5 28.9 65.1 28.5 17.25 100 94.031 149 80.3 29.2 64.9 28.5 17.43 110 82.5 31 153 80.2 29.2 65.1 28.419.60 120 78.3 25 152 79.9 30.0 64.9 28.9 19.08 130 66.4 25 153 79.929.2 64.9 28.4 19.24 141 66.3 25 152 79.8 29.8 65.1 28.6 19.29 150 66.125 153 80.2 29.7 64.9 28.7 18.44 160 65.7 25 152 80.1 29.6 65.1 28.518.43 170 66.1 25 153 80.1 30.0 65.1 28.8 18.85 181 57.7 25 152 79.929.4 64.8 28.4 — 191 76.9 25 154 80.0 29.4 65.0 28.3 16.70 200 63.9 25153 80.0 30.2 65.0 28.7 18.64 210 — — 150 74.6 31.0 — 28.0 16.97 220 — —150 80.7 37.1 — 31.7 14.95 Final 13.30 LOD =

The results showed a reduced surface area between the pre-granulated andpost-granulated materials and are depicted in Table 25, Sample 1. Table25, samples 2 and 3 also show a surface area of over 10 m²/g, whichcorresponds to rapid immediate release formulation characteristics asdescribed herein. The difference in granule particle surface area isnearly two orders of magnitude over granules that were prepared withincreased water as measured by LOD %.

TABLE 25 Sample Sample 1 BET Sample 2 BET Sample 3 BET Surface AreaSurface Area Surface Area (m²/g) (m²/g) (m²/g) Pre- 28.87 28.87 28.87granulation (API + ProSolv) Post_Granulation 11.85 14.03 10.18PTL_Report_Number 19005 19005 19005

A significant increase in particle surface area corresponded to areduction in particle size. Tablets with higher granular surface areahad a faster dissolution rate when compared to tablets prepared with alower granular surface area per unit weight.

Calcium stearate and sodium stearyl fumarate were added as lubricants.The quantity used in the formula are beyond the quantities recommendedin the art (e.g., Handbook of Pharmaceutical Excipients fifth edition);0.5% w/w of sodium stearyl fumarate or 2.4% w/w of calcium stearate wasused.

Example 10

A ferric citrate tablet was produced for clinical study as describedabove. The quantities of tablet components used are depicted in Table26.

TABLE 26 Material Description Target % w/w Individual kg/Batch TabletFerric Citrate 14.89 87.6 Pregelatinized Starch 1.70 10.0 CalciumStearate 0.406 2.4 Purified Water 15.30 N/A Core Tablet Total 17.00100.0 Opadry Purple 0.51 15.0 Purified Water 2.89 85.0 Coated TabletTotal 17.5 100.0Pregelatinized starch was sprayed into a chamber maintained at inlettemperature and product temperature. The LOD % water at every stage ofpreparation was maintained under 20%. The parameters used during theformulation are disclosed in Table 27.

TABLE 27 Spray Ex- Rate Pump Inlet Inlet Product Atom haust Time (g/Speed Air Temp Temp Air LOD Temp (min) min) (rpm) (SCFM) (° C.) (° C.)(psi) (%) (° C.) 0 — 38 150 61.5 42.6 60 11.24 41.3 10 107.6 38 151 63.031.3 60 12.4 34.5 20 109.1 38 151 63.1 27.1 60 13.32 29.5 30 109.5 38150 63.0 26.1 60 14.37 27.5 40 109.5 38 151 63.0 25.5 60 15.64 26.4 50109.6 38 151 62.9 25.3 60 16.99 25.7 60 109.5 38 152 69.4 25.9 60 17.6625.5 71 109.9 38 153 72.8 26.9 60 19.35 26.3 80 94.7 30 153 72.3 26.9 6017.05 26.3 90 91.0 35 151 71.7 27 60 19.66 26.3 100 88.5 30 152 72.127.1 60 19.57 26.3 110 81.7 30 150 73.3 27.4 60 18.88 26.4 120 85.7 33153 73.2 27.7 60 16.39 26.6 130 97.9 35 149 72.4 27.4 60 18.87 26.5 14194.5 33 152 72.0 27.4 60 18.78 26.3 150 93.3 34 153 71.9 27.3 60 18.6226.3 160 93.4 34 152 71.8 27.5 60 18.30 26.3 170 95.6 34 154 72.2 27.560 19.49 26.4 180 — — 151 71.9 29.5 — 16.71 26.8The targeted peak moisture between 19-20% (LOD) was achieved with amoisture content of 19.66% (LOD). Table 28 and Table 29 summarize thephysical properties after the granulation step and after the tabletingand drying steps.

TABLE 28 Granulation Characteristics ScreenSize % Retained 35_(500 μm)0.0 45_(355 μm) 1.3 60_(250 μm) 11.1 80_(180 μm) 16.2 120_(125 μm)  19.4170_(90 μm)  16.0 230_(63 μm)  16.3 Pan 18.8

TABLE 29 Final blend (post-tableting and drying) characteristicsBulk_Density_(g/ml) 0.460 Tapped_Density_(g/ml) 0.566 Hausner_Ratio 1.23Carr_Index 19Table 30 and Table 31 summarize the final blend characteristics of theformulations.

TABLE 30 Final Blend Characteristics Screen_Size % Retained 35_(500 μm)0.0 45_(355 μm) 0.8 60_(250 μm) 10.8 80_(180 μm) 16.6 120_(125 μm)  20.3170_(90 μm)  17.2 230_(63 μm)  15.6 Pan 17.0

TABLE 31 Test Results Bulk_Density_(g/ml) 0.436 Tapped_Density_(g/ml)0.573 Hausner_Ratio 1.31 Carr_Index 24

TABLE 32 Attribute_or_Setting Start Middle End Press_Main_Force(kN) 9.99.9 — Press_Pre_Force_(kN) 3.5 4.0 — Press_Speed_(rpm) 28.69 28.69 —Friability_(%) 0.2 — — Disintegration(seconds) 88 95 105

TABLE 33 Characteristic Weight Thickness Hardness Mean 1161 7.709 15.7Standard_Deviation 9.39 0.029 1.13 Min_Individual 1150 7.680 13.8Max_Individual 1186 7.800 18.0 RSD 0.81 0.38 7.20 Cpk 1.88 2.21 1.26The compression data demonstrates that the subject formulation andprocess were capable of producing a robust tablet with rapiddisintegration. The Cpk value for individual tablet weight demonstratesthe process was capable of consistently producing tablets within aspecification of ±5% of target. The tablet thickness and tablet hardnessmet the specified acceptance criteria.Coating and Drying Operating Parameters:The Opadry® coating suspension was prepared to 15% solids content byweight. The theoretical weight gain for the subject batch was 3%. Thefilm coating was a non-functional component used for aesthetics purposesonly and therefore the actual weight gain was not critical to drugperformance. The process sprayed to the theoretical quantity of coatingsuspension and not to a specific weight gain (an efficiency factor wasnot used). The average coated tablet weight post drying was 1110 mg.The operating parameters in Table 34 were used during the coatingprocess:

TABLE 34 Ex- Inlet Dew haust Spray Atom Pan Time AirFlow Temp Point TempRate Air Speed (min.) (cfm) (° C.) (° C.) (° C.) (g/min) (psi) (rpm) 0308 55.0 4.9 33.2 45 37 10 15 317 46.0 5.6 36.4 48 37 10 30 307 45.1 6.337.3 44 37 10 45 309 50.4 7.6 34.6 40 37 10 60 307 44.4 7.6 36.7 51 3710 75 310 52.9 7.5 37.3 53 37 10The operating parameters in Table 35 were used during the final tabletdrying process:

TABLE 35 Air Inlet Exhaust Time Flow Temp DewPoint Temp % Water (min)(cfm) (° C.) (° C.) (° C.) (LOD) 0 503 70.2 7.3 50.6 13.19 15 504 69.77.2 63.3 11.93 30 494 69.6 7.2 65.4 11.33 45 502 69.6 7.0 66.3 11.14 60500 70.4 6.8 67.0 10.14 75 502 80.1 7.0 73.0 9.73 90 501 80.2 7.0 74.59.59 105 505 79.7 6.8 75.4 8.96 120 509 81.1 6.8 75.7 8.78 135 510 81.26.6 76.2 8.21 150 505 81.1 6.7 76.5 7.88

The dissolution profiles demonstrate that higher moisture levels in thetablet can reduce the dissolution rate over time. Tablets with highmoisture content exposed to high temperature experienced acceleratedreductions in dissolution rate. The post-dried tablet, which had an endmoisture content of 8.84% (LOD), did not experience the same reductionin dissolution rate. The tablets containing high moisture level andcalcium stearate experienced the greatest reduction in dissolution rate.

The core and coated tablets containing calcium stearate had slightlyhigher moisture contents (˜15% LOD) when compared to the core tabletscontaining sodium stearyl fumarate (˜14% LOD). Without wishing to beheld to a particular theory or mode of action, this could becontributing to the difference in the observed dissolution rates. Thefinal moisture content of the tablet and moisture in the tablet duringmanufacture appear to contribute to the immediate releasecharacteristics and long term stability of the tablet.

The one month stability profile of pre-dried and post-dried tablets'stability were measured. The stability included both 25° C./60% RH and40° C./75% RH conditions. All samples were placed into HDPE bottles(0.025″ wall thickness) with a foil induction seal cap, and a smallportion of the study included bottles with desiccants. The followingcharts summarize the informal stability data.

With reference to FIG. 10, the immediate dissolution rate (greater than80% at 60 minutes after administration) of tablets exposed to thepost-dry process was maintained. The dissolution rate reduceddramatically after one week at in the absence of the post-dry process.

Example 11: Clinical Study of Ferric Citrate Dosage Forms

A protocol for performing clinical studies of a ferric citrate drugformulation as described above is provided as follows.

The protocol includes a 6-Week Feasibility Trial of a New Formulation ofKRX-0502 (Ferric Citrate) in Patients with End-Stage Renal Disease(ESRD). The objective of the study is to determine the potentialefficacy as a dietary phosphate binder and tolerability of KRX-0502(ferric citrate) in controlling and managing serum phosphorus levels inpatients with end-stage renal disease (ESRD) and monitoring the changein serum phosphorus from baseline to end of treatment after a four weektreatment period.

The study design includes conducting the study of the drug in patientswith ESRD on thrice weekly hemodialysis. Approximately 24 patients(twelve diabetic and twelve non-diabetic patients) will be initiated onstudy drug over two to three weeks.

The study consists of five periods: Screening, Washout, Study DrugInitiation, Treatment, and Final Visit. The two-week washout period isimmediately followed by a six-week treatment period. The duration of theclinical trial is approximately three to four months with approximatelytwo to three weeks being allocated for patient screening, washout, andinitiation of the study drug.

The study population includes all ESRD patients on thrice weeklyhemodialysis for at least three months prior to the Study DrugInitiation Visit (Visit 3) who are currently taking at least threetablets/capsules per day of calcium acetate, calcium carbonate,lanthanum carbonate or sevelamer (hydrochloride or carbonate) or anycombination of these agents will be eligible for enrollment.Approximately twelve patients will be diabetic and twelve patients willbe non-diabetic. Approximately 24 to 48 patients will be screened toinitiate approximately 24 patients on study drug. All patients will berecruited from 2-4 sites.

The study for the drug administration includes initiating approximately24 patients on KRX-0502 (ferric citrate) following a two week washoutperiod from their current phosphate binder and monitoring the serumphosphorus level during the study. The target level of serum phosphorusis approximately 3.5 to 5.5 mg/dL. The serum phosphorus levels will bechecked weekly during the washout period and during the visits 4, 5, 6,and at the Final Visit (Visit 7) of the treatment period.

The KRX-0502 dosage is determined by initiating all patients on thestudy drug with a fixed dosage of 6 tablets per day with each tablet offerric citrate containing 210 mg of ferric iron as ferric citrate(approximately 1260 mg of ferric iron as ferric citrate) and titratingthe blood samples of the patients at Visits 4, 5, and 6 as follows:

For a serum phosphorus level from 3.5-5.5 mg/dL of the blood, no actionis required, for a rise to >5.6-6.9 mg/dL, the drug dosage is increasedby one tablet per day and for a rise to 6.9 mg/dL, the dosage isincreased to 3 tablets per day to a maximum of 12 tablets/day.

Patients take the study drug orally with meals or snacks or within onehour after their meals or snacks. Patients are instructed not to takethe study drug if greater than one hour has passed since the ingestionof their meals or snacks. Some patients can require a differentdistribution in tablets in a given day due to snacks or missed meals.For example, if the patient is receiving a starting dose of 6 g/day thatpatient can be taking 2 tablets with breakfast, 2 with lunch, and 2 withdinner and can be switched to 1 with breakfast, 1 with a morning snack,1 with lunch, 1 with a afternoon snack and 2 with dinner if dietdictates.

The second phase of the study in the statistical plan, the drug efficacystudy, assesses the tolerability and safety of the study drug. Drugsafety is assessed by recording and monitoring adverse events, reviewingconcomitant medication use, conducting brief physical examinations(weight, blood pressure and heart rate), and obtaining sequential bloodchemistries (including serum phosphorus, serum calcium and selected ironparameters) and rates of adverse events and changes in laboratoryparameters.

While several particular forms of the disclosure have been illustratedand described, it will be apparent that various modifications andcombinations of the disclosure detailed in the text and drawings can bemade without departing from the spirit and scope of the disclosure. Forexample, references to materials of construction, methods ofconstruction, specific dimensions, shapes, utilities or applications arealso not intended to be limiting in any manner and other materials anddimensions could be substituted and remain within the spirit and scopeof the disclosure.

What is claimed is:
 1. A method for the prophylaxis or treatment ofhyperphosphatemia comprising administering to a patient in need thereofa ferric citrate tablet, wherein the ferric citrate tablet comprises:(a) a core comprising approximately 90% to approximately 92% by weightof ferric citrate, approximately 4.5% to approximately 30% by weight ofpregelatinized starch, and approximately 0.5% to approximately 3% byweight of a lubricant; and (b) a coating, wherein the tablet has afriability equal or less than 1% w/w, and wherein at least 80% of theferric citrate in the tablet is dissolved in less than or equal to 60minutes as measured by test method USP <711>, and the moisture contentof the tablet is less than 10% by loss on drying (LOD).
 2. The method ofclaim 1, wherein the lubricant is calcium stearate.
 3. The method ofclaim 1, wherein the tablet comprises approximately 1000 mg of ferriccitrate.
 4. A method for the prophylaxis or treatment ofhyperphosphatemia comprising administering to a patient in need thereofa ferric citrate tablet containing approximately 210 mg of ferric iron,wherein the ferric citrate tablet comprises: (a) a core comprisingapproximately 87.6% by weight of ferric citrate, approximately 10% byweight of pregelatinized starch, and approximately 2.4% by weight ofcalcium stearate; and (b) a coating, wherein the tablet has a friabilityequal or less than 1% w/w and a disintegration time less than 15minutes, and wherein at least 80% of the ferric citrate in the tablet isdissolved in less than or equal to 60 minutes as measured by test methodUSP <711>, and the moisture content of the tablet is 8.84% (LOD).
 5. Amethod for the prophylaxis or treatment of hyperphosphatemia comprisingadministering to a patient in need thereof a ferric citrate tablet,wherein the ferric citrate tablet comprises: (a) a core comprisingapproximately 90% to approximately 92% by weight of ferric citrate,approximately 4.5% to approximately 30% by weight of pregelatinizedstarch, and approximately 0.5% to approximately 3% by weight of alubricant; and (b) a coating, wherein the tablet has a friability equalor less than 1% w/w, and wherein at least 80% of the ferric citrate isdissolved in less than or equal to 60 minutes as measured by test methodUSP <711>, and the moisture content of the tablet is between 5% to 10%by LOD.
 6. The method of claim 5, wherein the lubricant is calciumstearate.
 7. The method of claim 5, wherein the tablet comprisesapproximately 1000 mg of ferric citrate.
 8. A method for the prophylaxisor treatment of hyperphosphatemia comprising administering to a patientin need thereof a ferric citrate tablet, wherein the ferric citratetablet comprises: (a) a core comprising approximately 90% toapproximately 92% by weight of ferric citrate, approximately 1.5% toapproximately 15% by weight of pregelatinized starch, and approximately0.5% to approximately 3% by weight of a lubricant; and (b) a coating,wherein the tablet has a friability equal or less than 1%, and whereinat least 80% of the ferric citrate in the tablet is dissolved in lessthan or equal to 60 minutes as measured by test method USP<711>, and themoisture content of the tablet is between 5% to 10% by LOD.
 9. Themethod of claim 8, wherein the lubricant is calcium stearate.
 10. Themethod of claim 8, wherein the tablet comprises approximately 1000 mg offerric citrate.
 11. A method for controlling serum phosphorus levels inan end-stage renal disease patient on hemodialysis comprisingadministering to the patent a ferric citrate tablet, wherein the ferriccitrate tablet comprises: (a) a core comprising approximately 90% toapproximately 92% by weight of ferric citrate, approximately 4.5% toapproximately 30% by weight of pregelatinized starch, and approximately0.5% to approximately 3% by weight of a lubricant; and (b) a coating,wherein the tablet has a friability equal or less than 1% w/w, andwherein at least 80% of the ferric citrate in the tablet is dissolved inless than or equal to 60 minutes as measured by test method USP <711>,and the moisture content of the tablet is less than 10% by loss ondrying (LOD).
 12. The method of claim 11, wherein the lubricant iscalcium stearate.
 13. The method of claim 11, wherein the tabletcomprises approximately 1000 mg of ferric citrate.
 14. A method forcontrolling serum phosphorus levels in an end-stage renal diseasepatient on hemodialysis comprising administering to the patent a ferriccitrate tablet containing approximately 210 mg of ferric iron, whereinthe ferric citrate tablet comprises: (a) a core comprising approximately87.6% by weight of ferric citrate, approximately 10% by weight ofpregelatinized starch, and approximately 2.4% by weight of calciumstearate; and (b) a coating, wherein the tablet has a friability equalor less than 1% w/w and a disintegration time less than 15 minutes, andwherein at least 80% of the ferric citrate in the tablet is dissolved inless than or equal to 60 minutes as measured by test method USP <711>,and the moisture content of the tablet is 8.84% (LOD).
 15. A method forcontrolling serum phosphorus levels in an end-stage renal diseasepatient on hemodialysis comprising administering to the patent a ferriccitrate tablet, wherein the ferric citrate tablet comprises: (a) a corecomprising approximately 90% to approximately 92% by weight of ferriccitrate, approximately 4.5% to approximately 30% by weight ofpregelatinized starch, and approximately 0.5% to approximately 3% byweight of a lubricant; and (b) a coating, wherein the tablet has afriability equal or less than 1% w/w, and wherein at least 80% of theferric citrate is dissolved in less than or equal to 60 minutes asmeasured by test method USP <711>, and the moisture content of thetablet is between 5% to 10% by LOD.
 16. The method of claim 15, whereinthe lubricant is calcium stearate.
 17. The method of claim 15, whereinthe tablet comprises approximately 1000 mg of ferric citrate.